The link between taking aspirin, non-steroidal anti-inflammatory drugs, or NSAIDS, and colorectal cancer prevention is well established, but the mechanisms behind the protective effect have not been understood. A new study, co-led by investigators at Fred Hutchinson Cancer Research Center and published March 17 in JAMA, suggests this protection differs according to variations in DNA.
"We've known for a very long time that aspirin, ibuprofen and other NSAIDs are protective for colorectal cancer, but they can't be used as a preventive agent because of the uncertainty of the risk-benefit ratio -- longtime use can lead to gastrointestinal bleeding and other side effects," said Ulrike "Riki" Peters, Ph.D., M.P.H., co-senior author of the paper and a cancer prevention researcher in the Public Health Sciences Division at Fred Hutchinson Cancer Research Center. "We wanted to investigate if genetic variation determined who is responding particularly well with aspirin -- for whom aspirin and NSAID use has particular benefit and for whom it doesn't."
For the study, Peters and colleagues -- including co-corresponding author and lead biostatistician Li Hsu, Ph.D., also of Fred Hutch, analyzed data from 10 large population-based studies in North America, Australia and Germany. They compared genetic and lifestyle data from 8,624 people who developed colorectal cancer with that of 8,553 people who did not (both groups were matched by age and gender).
While regular use of aspirin and NSAIDS was associated with an overall reduced risk of colorectal cancer, the researchers found no such protective effect among about 9 percent of the study participants who had genetic variations on chromosome 15. What's more, about 4 percent of the participants who carried two even rarer genotypes on chromosome 12 had an increased risk of colorectal cancer.
Understanding the interplay between such genetic variations and the use of aspirin and NSAIDs, also known as "gene-by-environment interactions," eventually may help identify those who could benefit most from these medications for cancer prevention as well as those who should steer clear of them.
"Our hope is that we can find a subgroup of the population where the benefits so outweigh the risks that it makes sense to take aspirin or NSAIDs," Peters said. "But we're not there yet."
Peters and colleagues are planning a larger follow-up study in the next several years with even greater statistical power to see if they can replicate their findings. "We would certainly like to validate the results … and truly see whether we can understand the biological mechanisms of these gene-by-environment interactions," Hsu said. "If it does hold true, it will have tremendous impact as to which subset of the group would benefit from using NSAIDs to reduce their [colorectal cancer] risk and in which group it may be harmful if they take NSAIDs.
"There's a long way between our finding and a public health impact, but that's the reason why we study the gene-by-environment interaction," Hsu said. Data for the study came from the Colorectal Cancer Family Registry, an international consortium coordinated by Fred Hutch; and the Genetics and Epidemiology of Colorectal Cancer Consortium, or GECCO. Fred Hutch houses GECCO's coordinating center; Peters is its principal investigator.
Collaborators included co-senior and co-corresponding author Andrew Chan, M.D., M.P.H. of the Massachusetts General Hospital; and first author Hongmei Nan, M.D., Ph.D., of Indiana University.
Support for the study included grants from the National Cancer Institute and the National Institute for Diabetes and Kidney Diseases, among other funding sources.
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